E2F-1 Regulates Nuclear Factor-κB Activity and Cell Adhesion

Abstract

Background-The transcription factor E2F-1 promotes vascular smooth muscle cell apoptosis and is reported to inhibit apoptosis induced by tumor necrosis factor (TNF)-␣ in endothelial cells. Whether E2F-1 overexpression exerts potentially antiinflammatory effects in endothelial cells is not known. Methods and Results-By immunoblotting and immunofluorescence, TNF-␣ treatment of human aortic endothelial cells (HAECs) with the control vector Ad.null was followed by rapid nuclear translocation of nuclear factor (NF)-B p65, whereas nuclear translocation of p65 was markedly reduced in HAECs overexpressing E2F-1. Electrophoretic mobility shift assay and gel shift analysis of nuclear cell extracts confirmed that HAECs treated with a recombinant adenovirus encoding E2F-1 failed to associate with the binding domain of p65. Stimulation of the Ad.null-infected endothelial cells with TNF-␣ resulted in enhanced expression of endothelial intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin and enhanced adhesion of monocytic U937 cells to the HAECs. Adhesion molecule expression and cell adhesion were reduced in E2F-1-transduced HAECs, associated with a marked decrease in phosphorylated IB-␣, required for nuclear translocation of NF-B p65. Conclusions-These

E2f1

“…20 Instructively, overexpression of E2F-1 in coronary vascular smooth muscle cells induces apoptosis, whereas E2F-1 overexpression exerts a survival effect in proliferating endothelial cells and restores cell-cycle progression of such cells. These observations, together with the findings by Chen et al, 13 support the theory that E2F-1 could serve as a "magic bullet" that exerts multiple beneficial effects in the vasculature, including inhibition of endothelial cell apoptosis, inhibition of smooth muscle cell proliferation, and inhibition of inflammatory cytokine and adhesion molecule expression, all of which prevent the development of atherosclerosis. Although further work is needed to dissect the pathways and mechanisms underlying the differential effects of E2F-1 in these different cellular activities with regard to the involvement of NFB or other transcription factors, as well as to examine the in vivo anti-atherogenic effects of E2F-1 overexpression, the intriguing discovery presented in this article 13 regarding the anti-inflammatory role of E2F-1 in relation to NFB activation certainly gives pause for thought.…”

“…Importantly, these authors showed that E2F-1 overepression in HAECs counteracted the TNF␣-induced endothelial intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression and inhibited the adhesion of monocytic U937 cells to HAECs. 13 These data provide evidence for an important link between cytokines, E2F1, NFB, and the proinflammatory transformation of endothelial cells, and suggest that E2F1 functions as an inhibitory regulator for NFB activation and the ensuing inflammatory response.…”

“…The article by Chen et al 13 demonstrates that adenovirusmediated gene transfer of E2F-1 markedly inhibits the phosphorylation of IB-␣ and reduces NFB p65 nuclear translocation in response to TNF␣ in human aortic endothelial cells (HAECs). This study reveals a novel function of E2F-1, the best characterized member of the E2F family of transcription factors, and positions E2F-1 as an inhibitor for NFB activation.…”

Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype

“…In line, it has been previously shown that local transfer of p16 INK4A into bone joints suppresses pro-inflammatory cytokines in a mouse model of rheumatoid arthritis [23] and that the E2F1 transcription factor, a target of p16 INK4A , is required for the transcriptional activation of certain NFκB target genes [24]. Moreover, the NFκB pathway has been shown, at least in mice, to play a role in ATM phenotype and function.…”

Métodos por imagem da aterosclerose em estudos de progressão/regressão: marcador substituto ou janela direta para o processo patológico da aterosclerose?

“…Current comprehensive approaches to risk reduction, including diet, exercise, and pharmacological intervention, decrease cardiovascular risk but do not prevent a substantial number of life-threatening cardiovascular events. Further improvements will require earlier diagnosis, a better understanding of the genetic predisposition 3,4 , and the development of novel pharmacological strategies to modify disease progression. Novel therapies require eventual proof of effectiveness in traditional mortality/morbidity endpoints trials, with large patient populations and long-term follow-up.…”